PT1524266E - Pharmaceutical composition - Google Patents

Description

ΡΕ1524266 1 DESCRIPTION " PHARMACEUTICAL COMPOSITION " The present invention relates to a composition comprising piperidine derivatives, and a selective serotonin reuptake inhibitor with processes for their preparation, pharmaceutical compositions containing them and their medical use.

In particular the invention relates to a composition comprising novel piperidine compounds which are potent and specific antagonists of tachykinins, including substance P and other neurokinins and a selective serotonin reuptake inhibitor. WO 97/16440 discloses substituted 1- (1,2-piperidinyl disubstituted) -4-piperazine derivatives of general formula

in which they are not inter alia 1, foot 1; Q is inter alia oxygen; X is a covalent bond or a bivalent radical 2 ΡΕ1524266 of the formula -O-, -S-, NR3; R 3 is hydrogen or a C 1-6 alkyl group; R1 is inter alia Ar1; R2 may be inter alia Ar2 C1-6 alkyl wherein Ar2 and Ar1 are inter alia a phenyl group which may be substituted with 1, 2 or 3 substituents each independently selected from halogen, C1-4 alkyl, halo C1-4 alkyl, L may be inter alia hydrogen, C1-6 alkyl or L is a radical of the formula - (CHR4) rC (O) YXR7, wherein r is 0,1,2,3 or 4, Y1 is inter alia NH or a N (C1-6 alkyl) ) or Y 1 is a covalent bond and R 7 is inter alia C 1-6 alkyl or C 3-7 cycloalkyl. The compounds are antagonists of tachykinins. We have now discovered a particular class of compounds that is not specifically disclosed here, whose class has special advantages. We have found that by selecting particular substituents (namely a piperazin-1-yl substituent at the 4-position of the piperidine ring, 1-substituted phenylalkylamide groups and 2-substituted phenyl groups) there is obtained a class of compounds having advantageous properties in the treatment of states mediated by tachykinins.

Thus the present invention provides a composition comprising a compound of formula (I) 3 ΡΕ1524266

in which R represents a halogen atom or a C 1-4 alkyl group; R1 represents a C1-4 alkyl group; R2 represents hydrogen or a C1-4 alkyl group; R3 represents hydrogen, or a C4-4 alkyl group; R4 represents a trifluoromethyl group; R5 represents hydrogen, a C1-4 alkyl group or C (O) R6, R6 represents C1-4 alkyl, C3-7 cycloalkyl, NH (C1-4 alkyl) or N (C1-4 alkyl) 2; m is zero or an integer from 1 to 3; n is an integer from 1 to 3; or pharmaceutically acceptable salts or solvates thereof and a selective serotonin reuptake inhibitor.

A further embodiment of the invention provides compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, wherein R 1 represents a halogen atom or a C 1-4 alkyl group;

R1 represents a C4-4 alkyl group; R 2 represents hydrogen or a C 1-4 alkyl group; 4 ΡΕ1524266 R3 represents hydrogen, or a C1-4 alkyl group; R4 represents a trifluoromethyl group; R5 represents hydrogen, a C1-4 alkyl or C (O) R6 group; R6 represents C1-4 alkyl, m is zero or an integer from 1 to 3; n is an integer from 1 to 3.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) include acid addition salts formed with pharmaceutically acceptable organic or inorganic acids, for example hydrochlorides, hydrobromides, sulfates, alkyl or arylsulfonates (eg methanesulfonates or p-toluenesulfonates), phosphates , acetates, citrates, succinates, tartrates, fumarates and maleates.

Solvates may, for example, be hydrates.

The references hereinafter to a compound of formula (I) according to the invention include both the compounds of formula (I) and their pharmaceutically acceptable acid addition salts together with pharmaceutically acceptable solvates.

Suitable pharmaceutically acceptable salts of the compounds of formula (I) may be obtained in a crystalline form and / or in an amorphous form or as a mixture thereof. 5 ΡΕ1524266

It will be understood by those skilled in the art that the compounds of formula (I) contain at least two chiral centers (notably the carbon atoms shown as in formula (I)) and these may be represented by formulas (1a, 1b, 1c and 1d ).

lc ld The wedge connection indicates that the bond is above the plane of the paper and is referred to as a β configuration. The broken connection indicates that the binding is below the paper cloth and is in the a configuration.

In general, in the specific compounds given below the β configuration at position 2 corresponds to the R configuration and the β configuration at position 4 corresponds 6 ΡΕ1524266 to the S configuration. The α configuration at position 2 corresponds to the S configuration and the α configuration at the 4 position corresponds to R configuration. The assignment of the R or S configuration in positions 2 and 4 was done according to the rules of Cahn, Ingold and Prelog, Experientia 1956,12,81. The configuration of the chiral carbon atoms of the piperidine ring shown in 1a and 1b is hereinafter referred to as the anti-configuration and in the formulas 1c and 1d as the sin configuration. Additional asymmetric carbon atoms in the compound of formula (I) are possible. Thus, when R 2 and R 3 are not the same group, the compounds of formula (I) have at least three asymmetric carbon atoms.

It should be understood that all enantiomers and diastereoisomers and mixtures thereof are included within the scope of the present invention. The term alkyl as used herein as a group or part of the group refers to a linear or branched alkyl group containing from 1 to 4 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl. The term halogen refers to a fluorine, chlorine, bromine or iodine atom. The term C 3-7 cycloalkyl group means a non-aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A preferred group of compounds of formula (I) are those in which the carbon atom at the 2-position of the piperidine ring is in the β-configuration. Within this group, those compounds wherein the carbon at the 4-position is in the β-configuration are particularly preferred.

When R 2 represents halogen this is suitably chlorine or more preferably fluorine or when R 2 is C 1-4 alkyl this is suitably methyl or ethyl wherein m is zero or an integer from 1 to 2.

Suitable values for R 2 or R 3 include hydrogen, a methyl group, an ethyl or a propyl. R is preferably a halogen (e.g. fluoro) and / or a C 1-4 alkyl group (e.g. methyl) and m is preferably zero or an integer of 1 to 2.

R1 is preferably a methyl group. R 2 is preferably a hydrogen atom or a methyl group. R 3 is preferably a hydrogen atom or a methyl group. Preferably R5 is a hydrogen, methyl, isopropyl or a C (O) cyclopropyl, a C (O) CH3, a C (O) NHCH3 or a C (O) N (CH3) 2 group.

A preferred class of compounds of formula (I) is that wherein each R is independently a halogen (eg fluorine) or a C 1-4 alkyl group (eg methyl), wherein m is 0, 1 or 2. More preferably m is 1 or 2. Within this class are particularly preferred those in which R 2 is in the 2-position and / or 4 in the phenyl ring.

Compounds of formula (I), wherein n is 2, represent a preferred class of compounds and within this class the R 4 groups are preferably in the 3 and 5 position on the phenyl ring.

A further preferred class of compounds of formula (I) is that wherein R 1 is methyl, R 2 or R 3 independently represents hydrogen or a methyl group.

A particularly preferred group of compounds of formula (I) is that in which each R is independently halogen or methyl in the 2-position and / or 4, the R 4 groups are in the 3 and 5-position, R 1 is methyl, R 2 and R 3 are independently hydrogen or methyl and R 5 is methyl, isopropyl or a C (O) cyclopropyl, a C (O) CH 3, a C (O) NHCH 3 or a C (O) N (CH 3) 2, m is 2 or 2 group. 9 ΡΕ1524266

Preferred compounds of formula (1) according to the invention are: 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) ) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- trifluoromethyl-benzyl) -methylamide; 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- trifluoromethyl-benzyl) -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (S) -piperazin-1-yl-piperidine-1-carboxylic acid, [1- (R) - (3,5-bis trifluoromethyl-phenyl) -ethyl) -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, 5-bis-trifluoromethyl-benzyl) -methylamide; 4- (S) - (4-Cyclopropanoylpiperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - (4-Cyclopropanoylpiperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - 10 Δ 1515266 (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -piperazine-1-carboxylic acid, dimethylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -1-carboxylic acid, methylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin-4-yl ] -piperazine; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethylphenyl) -ethyl] -methylamide; and their pharmaceutically acceptable salts or solvates (e.g., hydrochloride, methanesulfonate, sulfate, p-toluenesulfonate).

Further preferred compounds of formula (I) of the invention are: 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine 1-carboxylic acid, methanesulfonate of 11 ε AND 1524266 [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, ) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- bis-trifluoromethyl-benzyl) -methylamide.

A particularly preferred compound of formula (I) of the invention is 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) - piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide methanesulfonate.

The compounds of formula (I) are antagonists of tachykinins, including substance P and other neuroquinines, both in vitro and in vivo, and are thus to be used in the treatment of tachykinin mediated states, including substance P and other neurokinins. The affinity for binding to the NK1 receptor was determined in vitro through the ability of the compounds to replace the [3H] -substance P (SP) of the recombinant human NK1 receptors expressed on the Chinese Hamster Ovary (CHO) cell membranes.

CHO cell membranes were prepared by using a modification of the method described by Dam T and Quirion R (Peptides, 7: 855-864, 1986). Thus the 12 ΡΕ1524266 ligand binding was performed in 0.4 ml of 50 mM HEPES, pH 7.4, containing 3 mM MnCl2, 0.02% BSA, [3H] -Substance P 0.5 nM Ci / mmol, Amersham), a final membrane concentration of 25 pg protein / ml, and the test compounds. Incubation continued at room temperature for 40 min. Non-specific binding was determined using excess Substance P (1 μΜ) and representing about 6% of the total binding. The compounds of formula (I) were further characterized in a functional assay for the determination of their inhibitory effect. Human-NKi-CHO cells were stimulated with P-Substance and receptor activation was assessed by measuring the accumulation of cytidinediphosphododecylglycerol (CDP-DAG), which is the liponucleotide precursor of phosphatidylinositol diphosphate. CDP-DAG accumulates in the presence of Li + as a consequence of receptor-mediated activation of phospholipase C (PLC) (Godfrey, Biochem., J., 258: 621-624, 1989). The method is described in detail by Ferraguti et al. (Mol. Cell Neurosci., 5: 269-276, 1994). The action of the compounds of formula (I) on the NK 1 receptor may be determined by the use of standard assays. Thus the ability to penetrate the central nervous system and to bind to the NK 1 receptor has been demonstrated in vivo by its inhibitory effect on the variation of the intracerebroventricular substance P-induced behavior in the gerbil, according to the paw tremor model gerbil as described by Rupniak & Williams, Eur. J. of Pharmacol., 1994. 13 ΡΕ1524266

The compounds of formula (I) of the invention are useful in the treatment of CNS disorders. In particular, they are useful in the treatment or prevention of major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, tachyonic characteristics, melancholic features, atypical or postpartum onset characteristics, treatment of anxiety and the treatment of panic disorders. Other pathologies included in the term major depressive disorders include dysthymic pathology with early or late onset and with or without atypical features, neurotic depression, post-traumatic stress disorder, and social phobia; dementia of the Alzheimer type, with early or late onset, with depressed disposition; vascular dementia with depressed disposition; alcohol, amphetamine, cocaine, hallucinogenic, inhalant, opioid, phencyclidine, sedative, hypnotic, anxiolytic, and other substances; schizo-affective pathology of depressed type; and adaptation pathology with depressed disposition. Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc. It has also been found that the compounds of formula (I) of the invention exhibit anxiolytic activity in standard tests. For example in the human threat test on marmosets (Costall et al., 1988). 14 ΡΕ1524266

The compounds of formula (I) of the invention are useful as analgesics. In particular they are useful in the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as brachial plexus; chronic pain such as arthritic pain such as occurring in osteoarthritis, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, fibromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS-related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy , phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, time-romandibular pain, maxillary sinus pain, migraine headache; toothache; cancer pain; pain of visceral origin; gastrointestinal pain; nerve compression pain; sports injury pain; dysmenorrhea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; lumbagoes e.g. spinal stenosis; prolapsed disc; sciatica; angina; ankylosing spondiolitis; drop; burns; healing pain; scabies; and thalamic pain such as post-thrombotic thalamic pain.

The compounds of formula (I) of the invention are also useful in the treatment of sleep disorders including dysomia, insomnia, sleep apnea, narcolepsy, and circadian rhythm disorders. 15 ΡΕ1524266

The compounds of formula (I) of the invention are also useful in the treatment or prevention of cognitive disorders. Cognitive pathologies include dementia, amnestic pathologies and cognitive pathologies not otherwise specified.

Additionally the compounds of formula (I) are also useful as memory enhancers and / or cognition in healthy humans without cognitive and / or memory deficit.

The compounds of formula (I) of the invention are also useful in the treatment of tolerance to and dependence on a number of substances. For example, they are useful in the treatment of addiction to nicotine, alcohol, caffeine, phencyclidine (compounds of the phencyclidine type), or in the treatment of tolerance to and dependence on opioids (e.g. hashish, heroin, morphine) or benzodiazepines; in the treatment of cocaine addiction, hypnotic sedative, amphetamine or amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) or a combination thereof.

The compounds of formula (I) of the invention are also useful as anti-inflammatory agents. In particular they are useful in the treatment of inflammation in asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and non-steroidal anti-inflammatory drug induced damage; inflammatory skin diseases such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and ocular and dental inflammation.

The compounds of formula (I) of the invention are also useful in the treatment of allergic disorders, in particular allergic skin disorders such as urticaria, and allergic airways pathologies such as rhinitis.

The compounds of formula (I) of the invention are also useful in the treatment of emesis, i.e. nausea, vomiting and vomiting. The assay includes acute emesis, delayed emesis and anticipatory eesis. The compounds of formula (I) are useful in the treatment of emesis however induced. For example, the immunoassay may be induced by drugs such as cancer chemotherapeutic agents such as alkylating agents, e.g. cyclophosphamide, carmustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mitomycin-C and bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and 5-fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g., irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic pathologies or by infection, e.g. gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular pathologies, such as motion sickness, dizziness, dizziness and Meniere's disease; postoperative disease; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g., altitude sickness); opioid analgesics, such as morphine; and gastro-esophageal reflux disease, acid indigestion, over-indulgence of food or drink, acid stomach, acrid stomach, sialorrhoea / regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn and dyspepsia.

The compounds of formula (I) of the invention are also useful in the treatment of gastrointestinal conditions such as irritable colon syndrome; skin conditions such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischemia such as cerebral vasospasm after subarachnoid hemorrhage; fibrous and collagen diseases such as scleroderma and eosinophilic fascioliase; pathologies related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough.

The compounds of formula (I) of the invention are of particular use in the treatment of depressive states, in the treatment of anxiety and panic disorders. The 18 ΡΕ1524266 depressive states include major depressive disorders including bipolar depression, unipolar depression, single or recurrent major depressive episodes with or without psychotic features, tachyonic characteristics, melancholic characteristics, atypical or onset characteristics postpartum, dysthymic disorder with onset precocious or late and with or without atypical characteristics, neurotic depression, post-traumatic stress disorder and social phobia; dementia of the Alzheimer's type, with early or late onset, with depressed disposition; vascular dementia with depressed disposition; alcohol-induced mood disorders, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics, and other substances; schizoaffective pathology of the depressed type.

The compounds of formula (I) of the invention may be administered in combination with other active substances such as 5HT3 antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline reuptake inhibitors (SNRIs), antidepressants tricyclic or dopaminergic antidepressants.

Suitable 5HT 3 antagonists which may be used in combination with the compounds of formula (I) of the invention include for example ondansetron, granisetron and metoclopramide. 19 ΡΕ1524266

Suitable serotonin agonists that may be used in combination with the compounds of formula (I) of the invention include sumatriptan, rauwolscin, yohimbine and metoclopramide.

Suitable SSRIs which may be used in combination with the compounds of formula (I) of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline and zimeldine.

Suitable SNRIs that may be used in combination with the compounds of formula (I) of the invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination with a compound of formula (I) of the invention include imipramine, amitriptyline, clomipramine and nortriptyline.

Suitable dopaminergic antidepressants which may be used in combination with a compound of formula (I) of the invention include bupropion and aminoptin.

It will be understood that the compounds of the combination or composition may be administered simultaneously (either in the same or different pharmaceutical formulations) or sequentially. Also provided as a further aspect of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of tachykinin mediated states, including substance P and other neurokinins.

In an alternative or additional aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of tachykinin mediated states, including substance P and other neurokinins, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

It will be understood that reference to treatment is intended to include prophylaxis as well as relief of established symptoms. The compounds of formula (I) may be administered as the raw chemical but the active component is preferably presented as a pharmaceutical formulation.

Accordingly, the invention also provides a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and may conveniently be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients. 21 ΡΕ1524266

Thus the compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product for constitution with water or other suitable vehicle prior to use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, 22 ΡΕ1524266 oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). The preparations may also contain buffers, flavoring, coloring and sweetening agents as appropriate.

The preparations for oral administration may be suitably formulated to give controlled release of the active compound.

For oral administration the composition may take the form of tablets or lozenges formulated in conventional manner.

The compounds of formula (I) may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multiple dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active component may be in powder form for constitution with a suitable carrier, e.g. sterile pyrogen-free water, prior to use.

The compounds of formula (I) may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g., eye, ear or nasal drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Ointments for ocular administration may be manufactured in a sterile manner using sterile components.

The lotions may be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. The droplets may be formulated with an aqueous or oily base also comprising one or more dispersing agents, stabilizing agents, solubilizing agents or suspending agents. They may also contain a preservative.

The compounds of formula (I) may also be formulated into rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

The compounds of formula (I) may also be formulated as depot preparations. Such sustained acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, 24 ΡΕ1524266 the compounds of formula (I) may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as slightly soluble derivatives, for example as a slightly soluble salt.

For intranasal administration, the compounds of formula (I) may be formulated as solutions for administration via a suitable metered dose or unit device or alternatively as a powder mixture with a vehicle suitable for administration using a suitable delivery device.

A proposed dose of the compounds is from 1 to about 1000 mg per day. It will be understood that routine dosage variations may be required depending on the age and condition of the patient and the precise dosage will ultimately be at the discretion of the attending clinician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected.

The compounds of formula (I), and salts and solvates thereof, may be prepared by the general methods outlined hereinafter. In the following description, the groups R 1, R 2, R 3, R 4, R 5, R 6 m and n have the meaning as previously defined for the compounds of formula (I) unless otherwise noted.

The compounds of formula (I) may be 25 ΡΕ1524266 prepared by reductive N-alkylation of a compound of formula (II),

with a piperazine derivative (III) in an aprotic solvent such as dichloroethane and in the presence of a suitable metal reducing agent such as sodium borohydride or sodium triacetoxyborohydride.

The compounds of formula (II) may be prepared by treatment of the compounds of formula (IV)

with triphosgene in an aprotic solvent such as dichloromethane and in the presence of an organic base such as triethylamine to form the intermediate carbonyl chloride compound (V) which may be isolated if required, followed by the reaction of compound (V) with amine compound (VI)

(VI) The reaction conveniently takes place in an aprotic solvent such as a hydrocarbon, a halogenated hydrocarbon such as dichloromethane or an ether such as tetrahydrofuran optionally in the presence of a base such as a tertiary amine e.g. diisopropylethylamine.

When it is desired to isolate a compound of formula (I) as a salt, for example a pharmaceutically acceptable salt, this may be achieved by reacting the compound of formula (I) in the form of the free base with a suitable amount of suitable acid and in a solvent such as an alcohol (eg ethanol or methanol), an ester (eg ethyl acetate) or an ether (eg diethyl ether or tetrahydrofuran).

Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods. 27 ΡΕ1524266

The compounds of formula (III), (IV), (V) and (VI) may be prepared by methods analogous to those used for known compounds.

The compounds of formula (I) may be readily isolated in association with solvent molecules by crystallization from or evaporation of a suitable solvent to give the corresponding solvates.

When a specific enantiomer of a compound of formula (I) is required, it may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods. Thus, for example, the specific enantiomers of the compounds of formula (I) may be obtained from the corresponding enantiomeric mixture of a compound of formula (I) using a chiral HPLC procedure.

Alternatively, the enantiomers of a compound of formula (I) may be synthesized from suitable optically active intermediates using any of the general procedures described herein.

Thus for example the required enantiomer can be prepared by the corresponding chiral piperidin-4-one of formula (IV) using the procedure described above to prepare compounds of formula (I) from compounds 28 ΡΕ1524266 (IV), followed by separation of the mixture diastereomeric mixture of a compound of formula (I) using a standard procedure.

The chiral compounds (IV) may be prepared from the corresponding racemic compound (IV) using standard procedures such as salt formation with a suitable optically active acid, separating the resulting diastereoisomeric salts by conventional means eg chromatography and crystallization followed by hydrolysis of the salts diastereoisomers. An optically active acid suitable for use in the process is L (+) mandelic acid.

In a further embodiment of the invention the chiral compound (IV) may be prepared using the Comins reaction as described in the Journal American Chemical Society 1994, 116, 4719-4728, followed by reduction of the 2,3-dihydro-1H- pyridin-4-one to the piperidin-4-one derivative. The reduction may be effected using hydrogen and a metal catalyst e.g. palladium on a suitable carrier e.g. carbon or alumina. The reaction is carried out in a solvent such as an ester e.g. ethyl acetate.

In a further embodiment of the invention the enantiomers of the compound of formula (I) may be prepared by reaction of a chiral amine (VI) using any of the above described procedures to prepare compounds of formula (I) from the amine (V ). The chiral amine (III) may be prepared from the corresponding racemic amine (III) using any of the conventional procedures such as salt formation with a suitable optically active acid. The invention is further illustrated by the following Intermediates and Examples which are not to be construed as a limitation of the invention.

In the Intermediates and Examples unless otherwise noted:

The melting points (m.p.) were determined on a Buchi apparatus and are uncorrected. T.A. or T.A. refers to ambient temperature.

Infrared (IR) spectra were measured in chloroform or nujol solutions on an FT-IR instrument. Proton Magnetic Resonance (NMR) spectra were recorded on Varian instruments at 400 or 500 MHz, chemical shifts are reported in ppm (δ) using the residual solvent line as the internal standard. The unfolding patterns are designated as s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad. Mass spectra (MS) were taken on a Quattro VG mass spectrometer. Optical rotations were determined at 20øC with a Jasco instrument 30 ΡΕ1524266 DIP360 (1 = 10 cm, cell volume = 1 ml, λ = 589 nm). Flash chromatography on silica gel was performed on 230-400 mesh silica gel supplied by Merck AG Darmstadt, Germany. T.l.c. refers to thin layer chromatography on 0.25 mm (60F-254 Merck) silica gel plates and visualized with UV light.

The solutions were dried over anhydrous sodium sulfate. The methylene chloride was redistilled over calcium hydride and the tetrahydrofuran was redistilled on sodium. The following abbreviations are used in the text: AcOEt = ethyl acetate, CH = cyclohexane, DCM = methylene chloride, DIPEA = N, N-diisopropylethylamine, DMF = N, ΛΓ-dimethylformamide, Et 2 O = diethyl ether, EtOH = ethanol, MeOH = methanol, TEA = triethylamine, THF = tetrahydrofuran.

Intermediate 1 1- (Benzyloxycarbonyl) -2- (4-fluoro-2-methyl-phenyl) -2,3-dihydro-4-pyridone

A small amount of iodine was added to a suspension of magnesium filings (13.2 g) in dry THF (300 ml) at rt under a nitrogen atmosphere, then the mixture was refluxed vigorously for 20 minutes. To this suspension, a 15% solution of 2β-bromo-5-fluoro-toluene (52.5 ml) in anhydrous THF (300 ml) was added. The suspension was heated under vigorous reflux until the brownish color disappeared. The remaining portion of the bromide solution was added dropwise over 1 hour to the refluxing suspension which was then stirred for 1 hour. This Grignard reagent solution was then added dropwise to the pyridinium salt obtained from benzyl chloroformate (48.7 ml) and 4-methoxypyridine (25 ml) in dry THF (900 ml) at -23 ° C. The solution obtained was stirred 1 hour at -20 ° C then warmed to 20 ° C, a 10% solution of hydrochloric acid (560 ml) was added and the aqueous phase was extracted with EtOAc (2 x 750 ml).

The combined organic extracts were washed with 5% sodium hydrogencarbonate solution (600 ml) and brine (600 ml) then concentrated partially in vacuo.

CH (400 ml) was added dropwise over 1 hour at 20 ° C and the resulting mixture was stirred 30 minutes and then filtered to give the title compound as a white solid (66 g). IR (nujol, cm-1): 1726 and 1655 (C = O), 1608 (C = C). NMR (d 6 -DMSO): δ (ppm) 8.19 (d, 1H); 7.31-7.18 (m, 5H); 7.08 (m, 2H); 6.94 (dt, 1H); 5.77 (d, 1H); 5.36 (d, 1H); 5.16 (2d, 2H); 3.26 (dd, 1H); 2.32 (d, 1H); 2.26 (s, 3H). MS (ES +): m / z = 340 [MH] +. 32 ΡΕ1524266

Intermediate 2

Method A 2-Methyl-4-fluoro-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (50 ml) and the solution was stirred at rt under an atmosphere of nitrogen. After 1 hour the mixture was heated to reflux for 16 hours and then allowed to cool to rt This solution was slowly added to a refluxing solution of p-toluenesulfonic acid (10.6 g) in dry benzene (50 ml) at reflux for 1 hour previously with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated solution of potassium carbonate and suspended in EtOAc (50 ml). The aqueous phase was extracted with EtOAc (3 x 50 mL) and Et 2 O (2 x 50 mL). The organic phase was dried and concentrated in vacuo to a thick yellow oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6 N hydrochloric acid solution (20 ml) and stirred at 60 ° C for 16 hours. The solution was made basic with solid potassium carbonate and extracted with DCM (5 x 50 ml). The combined organic phases were washed with brine (50 ml), dried and concentrated in vacuo to give the title compound (2.5 g) as a thick yellow oil. 33 ΡΕ1524266

Method B

L-selectride (1M solution in dry THF, 210 ml) was added dropwise over 80 minutes to a solution of intermediate 1 (50 g) in dry THF (1065 ml) previously cooled to -72øC under an atmosphere of nitrogen.

After 45 minutes, 2% sodium hydrogencarbonate solution (994 ml) was added dropwise and the solution was extracted with AcOEt (3 x 994 ml). The combined organic phases were washed with water (284 ml) and brine (568 ml). The organic phase was dried and concentrated in vacuo to give 1-benzyloxycarbonyl-2- (4-fluoro-2-methyl-phenyl) -piperidin-4-one as a light yellow thick oil (94 g) which was used as a raw material.

This material (94 g) was dissolved in AcOEt (710 ml), then 10% Pd / C (30.5 g) was added under a nitrogen atmosphere. The slurry was hydrogenated at 1 atmosphere for 30 minutes. The mixture was filtered through Celite and the organic phase was concentrated in vacuo to give crude 2- (4-fluoro-2-methylphenyl) -piperidin-4-one as a yellow oil. This material was dissolved in AcOEt (518 mL) at r.t. and racemic camphorsulfonic acid (48.3 g) was added. The mixture was stirred at r.t. The solid was collected by filtration, washed with EtOAc (2 x 50 ml) and dried in vacuo for 18 hours to give 2- (4-fluoro-2-methylphenyl) -piperidin-4-one, 10-camphorsulfonic acid as a pale yellow solid (68.5 g). (Mp: 167-169 ° C-NMR (d6-34 ΡΕ1524266 DMSO): δ (ppm) 9.43 (broad s, 1H), 9.23 (bs, 1H), 7.66 (dd, 1H) (M, 2H), 2.97 (m, 3H), 2.66 (m, 1H), 2.53 (m, 2H), 2.37 (s, d, 4H), 2.22 (m, 1H), 1.93 (t, 1H), 1.8 (m, 2H) 2H), 1.03 (s, 3H), 0.73 (s, 3H).

This material (68.5 g) was suspended in AcOEt (480 ml) and stirred with saturated sodium hydrogencarbonate (274 ml). The organic phase was separated and washed with additional water (274 ml). The organic phase was dried and concentrated in vacuo to give the title compound (31 g) as a yellow-orange oil. NMR (d 6 -DMSO): δ (ppm) 7.49 (dd, 1 H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (broad m, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H). MS (ES +): m / z = 208 [MH] +.

Intermediate 3 2- (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl) -methylamide.

A solution of triphosgene (1.43 g) dissolved in dry DCM (10 ml) was added to a solution of intermediate 2 (2.5 g) and DIPEA (8.4 ml) in dry DCM (20 ml) previously cooled to 0 ° C under a nitrogen atmosphere. The solution was stirred at 0 ° C for 2 hours, then (3,5-bis-ΡΕ1524266 trifluoromethyl-benzyl) -methylamine hydrochloride (5.63 g) and DIPEA (3.34 ml) were added. The mixture was stirred under nitrogen at r.t. for 14 hours. The mixture was quenched with EtOAc (50 mL), washed with cold 1N hydrochloric acid solution (3 x 20 mL) and brine (10 mL). The organic phase was washed and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / CH 3: 7) to give the title compound as a white foam (3.85 g). IR (nujol, cm -1): 1721 and 1641 (C = O). NMR (de-DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.25 (dd, 1H); 6.97 (dd, 1H); 6.90 (dt, 1H); 5.22 (t, 1H); 4.59 (d, 1H); 4.43 (d, 1H); 3.63-3.49 (m, 2H); 2.79 (s, 3H); 2.69 (m, 2H); 2.49 (m, 2H); 2.26 (s, 3H). MS (ES +): m / z = 491 [MH] +.

Intermediate 4 2- (R) - (4-fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid, [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl ] -methylamide (4a) and 2- (S) - (4-fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid, [1- (R) -3,5-bis-trifluoromethyl -phenyl) -ethyl] -methylamide (4b)

Method A

A solution of triphosgene (147 mg) dissolved in 36 ΡΕ1524266 dry DCM (5 ml) was added dropwise to a solution of intermediate 2 (250 mg) and DIPEA (860 L) in dry DCM (15 ml) previously cooled to 0 ° C under a nitrogen atmosphere. After 2 hours, [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (503 mg) and DIPEA (320 μ) in dry acetonitrile (20 ml) were added and the mixture was heated at 70 ° C for 16 hours. Additional 1 - (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (170 mg) and DIPEA (100 μ) were added and the mixture was stirred at 70 ° C for 4 hours additional. The mixture was then allowed to cool to rt, suspended with EtOAc (30 ml), washed with cold 1N hydrochloric acid solution (3 x 15 ml) and brine (2 x 10 ml) . The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt 8: 2) to give: 1. intermediate 4a (230 mg) as a white foam, 2. intermediate 4b ( 231 mg) as a white foam.

Intermediate 4a NMR (de-DMSO): δ (ppm) 7.98 (broad s, 1H); 7.77 (br s, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1 H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H). 37 ΡΕ1524266

Intermediate 4b NMR (d6-DMSO): δ (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98 (dd, 1H); 6.93 (dt, 1H); 5.29 (q, 1H); 5.24 (t, 1H); 3.56 (m, 1 H); 3.48 (m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H).

Intermediate 4a

Method B

A saturated solution of sodium hydrogen carbonate (324 ml) was added to a solution of intermediate 9 (21.6 g) in AcOEt (324 ml) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous phase was further extracted with additional EtOAc (216 ml) and the combined organic extracts were dried and concentrated in vacuo to give intermediate 8 as a yellow oil, which was treated with TEA (19 ml) and AcOEt (114 ml). The solution obtained was added dropwise over 40 minutes to a solution of triphosgene (8 g) in EtOAc (64 ml) previously cooled to 0øC under a nitrogen atmosphere, maintaining the temperature between 0øC and 8øC.

After stirring for 1 hour at 0 ° C and for 3 hours at 20 ° C, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (29.7 g ), AcOEt (190 ml) and TEA (38 ml) were added to the reaction mixture which was then heated at reflux for 16 hours. 38 ΡΕ1524266 The solution was washed with 10% sodium hydroxide solution (180 ml), 1% hydrochloric acid solution (4 x 150 ml), water (3 x 180 ml) and saturated aqueous sodium chloride solution (180 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified through a silica slurry (CH / AcOEt 9: 1) to give the title compound (21.5 g) as a brown thick oil. NMR (d 6 -DMSO): δ (ppm) 7, 97-7, 77 (broad s + br, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H).

Intermediate 5

Carboxylic acid, [1- (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (5a) and 2- (R) - (4-fluoro-2-methyl- 1-carboxylic acid, [1- (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (5b)

A solution of triphosgene (147 mg) dissolved in dry DCM (5 ml) was added to a solution of intermediate 2 (250 mg) and DIPEA (860 μ) in dry DCM (15 ml) previously cooled to 0øC under an atmosphere of nitrogen. After 2 hours, a solution of 39 ΡΕ1524266 [1- (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (510 mg) and DIPEA (320 μΐ) in dry acetonitrile 20 ml) and the mixture was heated at 70 ° C for 16 hours. Subsequently, additional 1 - (S) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamine hydrochloride (170 mg) and DIPEA (105 μ) were added. After an additional 4 hours at 70 ° C, the mixture was allowed to cool to rt, suspended with EtOAc (30 ml), washed with 1N hydrochloric acid solution (3 x 15 ml) and brine ( 2 x 10 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt 8: 2) to give: 1 intermediate 5a (234 mg) as a white foam, intermediate 5b ( 244 mg) as a white foam.

Intermediate 5a NMR (d6-DMSO): δ (ppm) 7.97-7.77 (broad s + br, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H) intermediate 5b NMR (d-DMSO): δ (ppm) 7.98 (bs, 1H); 7.77 (br s, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1 H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 3H). 40 ΡΕ1524266

Intermediate 6 2- (S) - (4-fluoro-2-methyl-phenyl) -4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid, (1R, 2S, 5R) - 2-isopropyl-5-methyl-cyclohexylic acid (6a) and 2- (R) - (4-fluoro-2-methyl-phenyl) -4-oxo-3,4-dihydro- 1-carboxylic acid, (1R, 2S, 5R) -2-isopropyl-5-methyl-cyclohexyl ester (6b)

A solution of 2-bromo-5-fluoro-toluene (3.68 g) in dry THF (10 ml) was dropwise over 30 minutes in a mixture of magnesium (525 mg) and iodine (1 crystal) in dry THF ml) preheated to 70 ° C under a nitrogen atmosphere. The mixture was stirred at 70 ° C for 1.5 hours, then allowed to cool to r.t.

A solution of (-) - menthyl chloroformate (3.53 ml) in dry THF (15 ml) was added to a solution of 4-methoxypyridine (1.52 ml) in dry THF (35 ml) previously cooled to -78 DEG Under a nitrogen atmosphere. After 15 minutes, the solution containing 4-fluoro-2-methyl-phenyl magnesium bromide was added dropwise, and the mixture was stirred at -78 ° C for 1 hour. The reaction was quenched by the addition of 1M hydrochloric acid solution (20 ml), warmed to r.t. and stirred at 23 ° C for 30 minutes. After extraction with 41 ΡΕ1524266

AcOEt (2 x 150 ml), the combined organic extracts were washed with brine (50 ml), dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / THF / toluene-8 : 1: 1) to give: 1. intermediate 6a (3.44 g yellow oil) 2. intermediate 6b (530 mg - white solid),

Intermediate 6a T.l.c .: CH / THF / toluene 7: 2: 1, Rf = 0.59. IR (nujol, cm -1): 1718 and 1675 (C = O). NMR (d 6 -DMSO): δ (ppm) 8.14 (d, 1H); 7.08 (dd, 1H); 7.02 (dd, 1H); 6.95 (m, 1H); 5.68 (d, 1H); 5.34 (d, 1H); 4.47 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.7 (m, 4H); 1.33 (m, 2H); 0.8 (m, 1H).

Intermediate 6b m.p .: 117-120 ° C. T.l.c .: CH / THF / toluene 7: 2: 1, Rf = 0.56. IR (nujol, cm -1): 1718 and 1669 (C = O). NMR (d 6 -DMSO): δ (ppm) 8.17 (d, 1H); 7.04-6.94 (m, 3H); 5.70 (d, 1H); 5.35 (d, 1H); 4.42 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.58-1.40 (m, 3H); 1.2-0.7 (m, 8H); 0.51-0.34 (broad s, 6H): 42 ΡΕ1524266

Intermediate 7 2- (R) - (4-Fluoro-2-methyl-phenyl) -2,3-dihydro-1H-pyridin-4-one

Sodium methoxide (100 mg) was added to a solution of intermediate 6b (170 mg) in MeOH (15 ml) under a nitrogen atmosphere. The mixture was refluxed for two hours, and the solvent was removed in vacuo. The residue was partitioned between water (10 ml) and AcOEt (15 ml). The phases were separated, and the aqueous phase was extracted with additional EtOAc (4 x 10 mL). The combined organic extracts were washed with a saturated aqueous solution of sodium chloride (10 ml), dried and concentrated in vacuo to give the title compound (145 mg) as a light yellow oil. NMR (d 6 -DMSO): δ (ppm) 7.71 (broad d, 1H); 7.45 (dd, 1H); 7.38 (t, 1H); 7.03 (m, 2H); 4.86 (dd, 1H); 4.77 (d, 1H); 2.42 (dd, 1H); 2.31 (m, 4H). MS (ES +): m / z = 206 [M + H] +. Intermediate 8 2- (R) - (4-Fluoro-2-methyl-phenyl) -piperidin-4-one

Palladium on charcoal (10% - 74 mg) was added to a solution of intermediate 7 (145 mg) in MeOH (8 mL) and THF (2 mL). The mixture was allowed to react with hydrogen in a pressure reactor (2 atm) overnight. 43 ΡΕ1524266

After washing with nitrogen, the solution was filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography (AcOEt / MeOH 9: 1) to give the title compound (26mg) as a yellow oil. Enantiomeric excess (90-95%) was detected by chiral HPLC. T.l.c .: AcOEt / MeOH 9: 1, Rf = 0.2. NMR (de-DMSO): δ (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (broad m, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H). MS (ES +): m / z = 208 [MH] +. [a] D = +82.1 (c = 1.07, DMSO).

Intermediate 9 2- (R) - (4-Fluoro-2-methyl-phenyl) -piperidin-4-one mandelic acid.

A solution of L - (+) - mandelic acid (22.6 g) in AcOEt (308 ml) was added to a solution of intermediate 2 (31 g) in AcOEt (308 ml). Isopropanol (616 ml) was then added and the solution was concentrated in vacuo to 274 ml. The solution was then cooled to 0øC and additional isopropanol (96 ml) was added. The thick precipitate was stirred under nitrogen for 5 hours at 0 ° C, then filtered and washed with cold Et 2 O (250 ml) to give the title compound as a light yellow solid (20.3 g). 44 ΡΕ1524266 P.f. : 82-85 ° C. NMR (de-DMSO): δ (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32 (m, 2H); 7.26 (m, 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H); 2.88 (m, 1H); 2.49-2.2 (m, 4H); 2.29 (s, 3H). Chiral HPLC: HP 1100 HPLC system; Chiralcel OD-H column, 25 cm x 4.6 mm; mobile phase: n-hexane / isopropanol 95: 5 + 1% diethylamine; flow rate: 1.3 ml / min; detection: 240/215 nm; retention time 12.07 minutes.

Intermediate 10 2- (R) - (4-Fluoro-2-methyl-phenyl) -4-oxo-piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl) -methylamide

Method A

A solution of triphosgene (17 mg) in dry DCM (2 ml) was added to a solution of intermediate 8 (26 mg) and DIPEA (65 mg) in dry DCM (3 ml) previously cooled to 0øC under an atmosphere of nitrogen. After two hours acetonitrile (10 ml) was added, the temperature was allowed to reach r.t. and the DCM evaporated under a stream of nitrogen. Thereafter, a solution of 3,5- (bis-trifluoromethyl-benzyl) -methylamine hydrochloride (74 mg) and DIPEA (130 mg) in acetonitrile (3 ml) was added and the mixture was stirred at 23 ° C overnight . The solvent was concentrated in vacuo. The residue was dissolved in AcOEt (10 ml) and washed with 1N hydrochloric acid solution (3x5 ml), 5% sodium hydrogen carbonate (5 ml) and brine (10 ml) ). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt 1: 1) to give the title compound (50 mg) as a white solid.

Method B

A saturated solution of sodium hydrogencarbonate (348 ml) was added to a solution of intermediate 9 (23.2 g) in AcOEt (348 ml) and the resulting mixture was stirred vigorously for 15 minutes. The aqueous phase was re-extracted with additional EtOAc (230 ml) and the combined organic extracts were dried and concentrated in vacuo to give intermediate 8 (12.31 g) as a yellow oil, which was treated with TEA (20.5 g ml) and AcOEt (123 ml). The solution obtained was added dropwise over 40 minutes to a solution of triphosgene (8 g) in AcOEt (61 ml), previously cooled to 0øC under a nitrogen atmosphere, maintaining the temperature between 0øC and 8øC.

After stirring for 2 hours at 20 ° C, 3,5- (bis-trifluoromethyl-benzyl) -methylamine hydrochloride (28.1 g), EtOAc (184 ml) and TEA (33 ml) were added to the reaction mixture which was then further stirred for 2 hours at 20 ° C. The solution was washed with 10% sodium hydroxide solution (3 x 185 ml) and 1% hydrochloric acid solution (3 x 185 ml). The organic phase was dried and concentrated in vacuo to a crude material (38 g), which was purified through a silica (CH / AcOEt from 9: 1 to 1: 1) to give the title compound (24 , 7 g) as a colorless oil. NMR (d 6 -DMSO): δ (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.26 (dd, 1H); 6.98 (dd, 1H); 6.90 (td, 1H); 5.23 (t, 1H); 4.61 (d, 1H); 4.41 (d, 1H); 3.60 (m, 2H); 2.69 (m, 2H); 2.79 (s, 3H); 2.50 (m, 2H); 2.27 (s, 3H). MS (ES +): m / z = 491 [MH] +.

Intermediate 11 4-Cyclopropanoyl-piperazine-1-carboxylic acid, tert-butyl ester

Cyclopropanoyl chloride (112 μ) was added to a mixture of N-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassium carbonate in anhydrous DCM (10 ml) under an atmosphere of nitrogen. The mixture was stirred at r.t. for 18 hours, then removed by filtration from the inorganics. The organic phase was diluted with Et 2 O (20 mL) and washed with 1N hydrochloric acid solution (10 mL). The aqueous phase was made basic with 1 N sodium hydroxide solution and extracted twice with DCM. The combined organic phases were dried and concentrated in vacuo to give the title compound (210 mg) as an oil. T.l.c .: AcOEt, Rf = 0.45. NMR (de-DMSO): δ (ppm) 3.64-3.28 (m, 8H); 1.94 (m, 1H); 1.4 (s, 9H); 0.7 (m, 4H). MS (ES +): m / z = 255 [M + H] +. 47 ΡΕ1524266

Intermediate 12 1-Cyclopropanoylpiperazine

TFA (965 μΐ) was added to a solution of intermediate 11 (210 mg) in anhydrous DCM (1 mL). The solution was stirred at r.t. for 2 hours, then concentrated in vacuo. The residue was diluted with saturated potassium carbonate solution (10 ml) and extracted with EtOAc (2 x 20 ml). The combined organic extracts were dried and concentrated in vacuo to give the title compound (110 mg) as an oil. T.l.c .: AcOEt, Rf = 0.14. IR (CDCl 3, ν n): 1626 (C = O). NMR (CDCl3): δ (ppm) 3.7 (broad s, 1H); 3.63 (broad d, 4H); 2.88 (broad d, 4H); 1.72 (m, 1H); 0.99 (m, 2H); 0.75 (m, 2H). MS (ES +): m / z = 155 [M + H] +.

Intermediate 13 4- (2-Methyl-propanoyl) -piperazine-1-carboxylic acid, tert-butyl ester

Isopropanoyl chloride (112 μ) was added to a mixture of N-tert-butoxycarbonylpiperazine (200 mg) and an excess of potassium carbonate in anhydrous DCM (10 ml) 48/1515266 under a nitrogen atmosphere. The mixture was stirred at r.t. for 18 hours, then removed by filtration from the inorganics. The organic phase was diluted with Et 2 O (20 mL) and washed with 1N hydrochloric acid solution (10 mL). The aqueous phase was made basic with 1N sodium hydroxide solution and extracted twice with DCM. The combined organic phases were dried and concentrated in vacuo and the residue purified by flash chromatography (100% EtOAc) to give the title compound (133 mg) as a white solid. T.l.c. : AcOEt, Rf = 0.58. IR (nujol, cm -1): 1703 and 1630 (C = O). NMR (d 6 -DMSO): δ (ppm) 3.45-3.4 (m, 4H); 3.3-3.26 (m, 4H); 2.84 (m, 1H); 1.4 (s, 9H); 0.97 (d, 6H). MS (ES +): m / z = 257 [M + H] +.

Intermediate 14: 1- (2-Methyl-propanoyl) -piperazine

TFA (900 μ) was added to a solution of intermediate 13 (133 mg) in anhydrous DCM (10 ml). The solution was stirred at r.t. for 3.5 hours, then concentrated in vacuo. The residue was diluted with saturated potassium carbonate solution (10 ml) and extracted with AcOEt (2 x 20 ml). The combined organic extracts were dried and concentrated in vacuo to give the title compound (50 mg) as an oil. 49 ΡΕ1524266 T.I.c .: AcOEt, Rf = 0.12. IR (CDCl3, cm-1): 1624 (C = O). NMR (CDCl3): δ (ppm) 3.7 (broad s, 2H); 3.5 (bs, 2H); 2.86 (m, 4H); 2.78 (m, 1H); 1.13 (d, 6H). MS (ES +): m / z = 157 [M + H] +.

Intermediate 15 4- (R) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -piperazine-1-carboxylic acid, tert-butyl ester (15a) and 4- (S) - [1 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- ( R) - (4-fluoro-2-methyl-phenyl) -piperidin-4-yl] -piperazine-1-carboxylic acid tert-butyl ester (15b)

A solution of intermediate 10 (400 mg) and N-tert-butoxycarbonylpiperazine (151.8 mg) and dry 1,2-dichloroethane (10 ml) was stirred at r.t. for 30 minutes under a nitrogen atmosphere. Thereafter, sodium triacetoxyborohydride (310 mg) was added and the mixture was stirred at 23 ° C for 24 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (AcOEt / MeOH 9: 1) to give: 1. intermediate 15a (181 mg), 2. intermediate 15b (155 mg) . 50 ΡΕ1524266

Intermediate 15a: T.l.c .: AcOEt / MeOH 8: 2 Rf = 0.35. IR (nujol, cm -1): 1703 and 1651 (C = O). NMR (de-DMSO): δ (ppm) 7.91 (s, 1H); 7.65 (s, 2H); 7.26 (dd, 1H); 6.89 (dd, 1H); 6.79 (bt, 1H); 4.78 (dd, 1H); 4.52 (d, 1H); 4.37 (d, 1H); 3.25 (m, 6H); 3.09 (m, 1H); 2.78 (s, 3H); 2.37 (broad s, 4H); 2.22 (s, 3H); 1.86 (m, 1H); 1.78 (m, 1H); 1.68 (m, 2H); 1.35 (s, 9H) MS (ES +): m / z = 661 [MH] +.

Intermediate 15b T.I.c .: AcOEt / MeOH 8: 2 Rf = 0.14. IR (nujol, cm -1): 1702 and 1654 (C = O). NMR (d 6 -DMSO): δ (ppm) 7.90 (s, 1H); 7.56 (s, 2H); 7.18 (dd, 1H); 6.85 (dd, 1H); 6.73 (dt, 1H); 4.59 (d, 1H); 4.32 (d, 1H); 4.1 (dd, 1H); 3.41 (broad m, 1H); 3.21 (s, 4H); 2.87 (s, 3H); 2.64 (t, 1 H); 2.5 (m, 1 H); 2.39 (broad s, 4H); 2.3 (s, 3H); 1.82 (bs, 1H); 1.73 (m, 1H); 1.56 (dq, 1H); 1.33 (s, 9H); 1.33 (q, 1H). MS (ES +): m / z = 661 [MH] +.

Intermediate 16 1- (Benzyloxycarbonyl) -2- (4-fluoro-phenyl) -2,3-dihydro-4-pyridone

A solution of benzyl chloroformate (48.7 ml) in a dry THF (60 ml) was added to a solution of 4-methoxypyridine (25 ml) in dry THF (900 ml) previously cooled at -23øC under atmosphere. The mixture was stirred at -23 ° C for 50 minutes, then p-fluorophenyl magnesium bromide (1M in THF - 48.7 ml) was added. The solution was stirred at -20 ° C for 1 hour, then warmed to 20 ° C and a solution of 10% hydrochloric acid (560 ml) was added. The aqueous phase was extracted with AcOEt (1000 ml). The organic extract was washed with 5% sodium hydrogencarbonate solution (600 ml) and brine (600 ml) then partially concentrated in vacuo.

CH (200 ml) was added dropwise over 1 hour at 20 ° C and the resulting mixture was stirred at r.t. for 10 minutes, then at 0 ° C for 1.5 hours. The solid obtained was removed by filtration to give the title compound as a white solid (51.6 g). NMR (de-DMSO): δ (ppm) 8.05 (d, 1H); 7.4-7.3 (m, 5H); 7.24 (dd, 2H); 7.15 (t, 1H); 5.73 (d, 1H); 5.29 (d, 1H); 5.24 (dd, 2H); 3.25 (dd, 1H); 2.62 (d, 1H); 2.26 (br, 3H). MS (EI / +): m / z = 325 [M] +.

Intermediate 17 1-Benzyloxycarbonyl 2- (4-fluoro-phenyl) -piperidin-4-one 52 ΡΕ1524266 L-selectride (1 M solution in THF, 62 ml) was added dropwise over 80 minutes to a solution of intermediate 16 (20 g) in dry THF (300 ml) previously cooled to -72 ° C under a nitrogen atmosphere. After 45 minutes, the solution was allowed to warm to -30 ° C and 2% sodium hydrogencarbonate solution (280 ml) was added dropwise. The solution was extracted with EtOAc (3 x 280 mL). The combined organic phases were washed with water (80 ml) and brine (160 ml). The organic phase was dried and concentrated in vacuo to give the title compound as a pale yellow oil (27 g). NMR (de-DMSO): δ (ppm) 7.26 (m, 7H); 7.17 (t, 2H); 5.53 (broad t, 1H); 5.12 (m, 2H); 4.1 (m, 1H); 3.44 (m, 1H); 3.01-2.84 (2dd, 2H); 2.54-2.3 (m, 2H).

Intermediate 17 (94 g) was dissolved in AcOEt (300 ml), then 10% Pd / C (6.8 g) was added under an atmosphere of nitrogen. The slurry was hydrogenated at 1 atmosphere for 3 hours. The mixture was filtered through Celite and the organic phase was concentrated in vacuo to give the crude 2- (4-fluoro-phenyl) -piperidin-4-one (10 g). A portion of this material (9 g) was purified by flash chromatography (from CH3 / EtOAc 7: 3 to 100% EtOAc) to give the title compound as a yellow oil (5 g). 53 ΡΕ1524266 NMR (d6 -DMSO): δ (ppm) 7.43 (m, 2H); 7.15 (m, 2H); 3.86 (dd, 1H); 3.29 (m, 1 H); 2.87 (bs, 1H); 2.81 (m, 1H); 2.48 (m, 1H); 2.42 (m, 1H); 2.33 (m, 1H); 2.19 (m, 1H).

Intermediate 19 2- (4-Fluoro-phenyl) -piperidin-4-one, L - (+) - mandelate L - (+) - mandelic acid (2.6 g) was added to a solution of intermediate , 3 g) in acetone (50 ml) at rt The mixture was stirred at rt for 3 hours and at 0 ° C for 30 minutes, then the solid was removed by filtration to give the title compound as a white solid (4.4 g).

Federal Police . : 123-124 ° C NMR (de-DMSO): δ (ppm) 7.39 (m, 2H); 7.35 (d, 2H); 7.27 (t, 2H); 7.2 (t, 1H); 7.11 (t, 2H); 4.86 (s, 1H); 3.83 (dd, 1H); 3.3-2.78 (m, 2H); 2.6-2.35 (m, 2H); 2.3-2.15 (m, 2H).

Intermediates 20a and 20b 2- (R) - (4-fluoro-phenyl) -4-oxo-piperidine-1-carboxylic acid, [1- (R) -3,5-bis-trifluoromethyl-phenyl) -ethyl ] -methylamide (20a) and 2- (S) - (4-fluoro-phenyl) -4-oxo-piperidine-1-carboxylic acid, [1- (R) -3,5-bis-trifluoromethyl-phenyl ) -ethyl] -methylamide (20b) Intermediate 19 (600 mg) was treated with a 54 ΡΕ1524266 potassium carbonate saturated solution (60 ml) and extracted with AcOEt (3 x 30 ml). The combined organic extracts were dried and concentrated in vacuo to give 2- (4-fluorophenyl) -piperidin-4-one (267 mg). A solution of triphosgene (205 mg) dissolved in dry DCM (2 ml) was added dropwise to a solution of 2- (4-fluorophenyl) piperidin-4-one (267 mg) and TEA (800 μ) in DCM (9 ml) previously cooled to 0øC under a nitrogen atmosphere. The mixture was stirred at 0 ° C for 3 hours and during this time additional TEA (800 μl) and triphosgene (205 mg) were added until complete disappearance of the starting material. Then [1- (R) -3,5-bis-trifluoromethylphenyl) -ethyl] -methylamine hydrochloride (560 mg) and DIPEA (1 ml) were added in dry acetonitrile (15 ml) and the mixture was heated to 70 ° C for 16 hours. The mixture was allowed to cool to r.t., quenched with EtOAc (30 mL), washed with cold 1N hydrochloric acid solution (3 x 15 mL) and brine (3 x 20 mL). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt 7: 3) to give: 3 intermediate 20a (140 mg) as a yellow oil, intermediate 20b ( 195 mg) as a yellow oil.

Intermediate 20a T.l.c .: CH / AcOEt 1: 1, Rf = 0.65. IR (film, cm -1): 1719 and 1636 (C = O). 55 ΡΕ1524266 NMR (de-DMSO): δ (ppm) 8.0 (s, 1H); 7.87 (s, 2H); 7.3 (dd, 2H); 7.11 (t, 2H); 5.19 (m, 2H); 3.68 (m, 1 H); 3.36 (m, 1 H); 2.8 (m, 2H); 2.66 (s, 3H); 2.58 (m, 1 H); 2.3 (m, 1H); 1.59 (d, 3H). MS (ES +): m / z = 491 [M + H] +.

Intermediate 20b T.I.c .: CH / AcOEt 1: 1, Rf = 0.49. IR (film, cm -1): 1721 and 1639 (C = O). NMR (de-DMSO): δ (ppm) 7.97 (s, 1H); 7.82 (s, 2H); 7.29 (dd, 2H); 7.1 (dd, 1H); 5.21 (q, 1H); 5.11 (t, 1H); 3.6 (m, 1 H); 3.46 (m, 1H); 2.85-2.7 (2dd, 2H); 2.76 (s, 3H); 2.56 (m, 1H); 2.39 (m, 1H); 1.54 (d, 3H). MS (ES +): m / z = 491 [m + H] +.

Example 1 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, ) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -ethyl] -2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl]

A solution of intermediate 4a (120 mg), 1-acetylpiperazine (29.8 mg) and sodium triacetoxyborohydride (126 mg) in dry 1,2-dichloroethane (5 ml) was stirred at 23 56 Ρ AND 1524266 ° C for 24 hours under a nitrogen atmosphere. The solution was washed with 5% sodium hydrogen carbonate solution (15 ml) and brine (10 ml). The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / MeOH 7: 3) to yield: 1. 4- (R) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (4-Acetyl-piperazin-1-yl) -2- (R) - (4-acetyl-piperazin-1-yl) fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (30.0 mg - Tlc: AcOEt / MeOH : Rf = 0.36).

Example 2 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide

A solution of example 1a (40.0 mg) in dry Et2O (5 ml) was treated with hydrochloric acid (1M in Et2O - 1 ml). The resulting solution was stirred at 23 ° C for 30 minutes, then concentrated in vacuo to give the title compound as a white solid (41.2 mg). IR (nujol, cm -1): 3416 (NH +), 1652 (C = O). 57 ΡΕ1524266 NMR (de-DMSO): δ (ppm) 10.35 (bs, 1H); 8.00 (s, 1H); 7.77 (s, 2H); 7.37 (dd, 1H); 7.01 (dd, 1H); 6.93 (dt, 1H); 5.25 (broad m, 1H); 5.06 (q, 1H); 4.44 (broad m, 1H); 3.99 (m, 1H); 3.70-3.45 (m, 4H); 3.20-2.90 (2m, 4H); 2.15 (m, 2H); 1.90-1.75 (2m, 3H); 2.04 (s, 3H); 1.57 (d, 3H). MS (ES +): m / z = 617 [MH-HCl] +.

Example 3 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide

A solution of Example 1b (30.0 mg) in dry Et 2 O (5 mL) was treated with hydrochloric acid (1 M in Et 2 O - 1 mL). The resulting mixture was stirred at 23 ° C for 15 minutes, then filtered; the filtrate was treated with additional Et 2 O 2 (2 mL) to give the title compound as an off-white solid (26.5 mg). IR (nujol, cm -1): 3383 (NH +), 1650 (C = O). NMR (de-DMSO): δ (ppm) 11.17 (broad s, 1H); 7.98 (s, 1H); 7.67 (s, 2H); 7.21 (t, 1H); 6.94 (dd, 1H); 6.82 (dt, 1H); 5.3 (q, 1H); 4.4 (broad d, 1H); 4.18 (dd, 1H); 3.96 - 3.42 (m, 5H); 3.10-2.70 (m, 4H); 2.72 (s, 3H); 2.43 (s, 3H); 2.17 (m, 2H); 2.00 (s, 3H); 1.73-1.24 (m, 3H); 1.45 (d, 3H). MS (ES +): m / z = 617 [MH-HCl] +. 58 ΡΕ1524266

Example 4 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide

A solution of intermediate 4a (7.7 g) in acetonitrile (177 ml) was added to a solution of 1-acetylpiperazine (3.9 g) in acetonitrile (17.7 ml) followed by sodium (6.4 g) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 24 hours and then quenched with saturated sodium hydrogencarbonate solution (23.1 ml) and water (61.6 ml). The resulting solution was concentrated in vacuo, then AcOEt (208 mL) was added; the phases were separated and the aqueous phase was re-extracted with additional EtOAc (2 x 77 ml). The collected organic phases were washed with brine (2 x 118 ml), dried and concentrated in vacuo to give the crude mixture of sin and anti (approx. 1: 1) diastereomers as a white foam ( 9.5 g).

A solution of this intermediate in THF (85.4 ml) was added to a solution of methanesulfonic acid (0.890 ml) in THF (6.1 ml) at rt. After nucleation the unwanted diastereomer began to precipitate. The resulting suspension was stirred for 3 hours at 0 ° C and 59 ° 1515266, then filtered under a nitrogen atmosphere. The resulting cake was washed with cold THF (15.4 ml) and dried in vacuo at + 20 ° C for 48 hours to give the title compound as a white solid (4.44 g). NMR (de-DMSO): δ (ppm) 9.52 (broad s, 1H); 7.99 (broad s, 1H); 7.68 (bs, 2H); 7.23 (m, 1H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.31 (q, 1H); 4.45 (broad d, 1H); 4.20 (dd, 1H); 3.99 (broad d, 1H); 3.65-3.25 (broad m, 5H); 3.17 (m, 1H); 2.96 (m, 1H); 2.88-2.79 (m + m, 2H); 2.73 (s, 3H); 2.36 (s, 3H); 2.30 (s, 3H); 2.13-2.09 (broad d + long d, 2H); 2.01 (s, 3H); 1.89-1.73 (m + m, 2H); 1.46 (d, 3H). mp 243.0 ° C. The compound is isolated in a crystalline form.

Example 5 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide

96% sulfuric acid (0.06 ml) was added to a solution of example 1b (0.65 g) in THF (6.5 ml) at 23øC under a nitrogen atmosphere. The suspension was stirred at 23 ° C for 15 hours, then cooled to 4 ° C, stirred for 4 hours and allowed to warm to rt. The solid was removed by filtration and dried at 23 ° C for 18 hours to give the title compound. (0.681 g). NMR (d 6 -DMSO): δ (ppm) 9.58 (broad s, 1H); 7.99 (broad s, 1H); 7.68 (bs, 2H); 7.23 (m, 1H); 6.95 (dd, 1H); 6.83 (m, 1H); 5.31 (q, 1H); 4.45 (broad d, 1H); 4.20 (d, 1H); 60 ΡΕ1524266 3.98 (bm, 1H); 3.65-3.30 (broad m, 5H); 3.20 - 2.70 (broad m, 4H); 2.74 (s, 3H); 2.36 (s, 3H); 2.13 (broad d, 1H); 2.08 (broad d, 1H); 2.02 (s, 3H); 1.87 (m, 1H); 1.72 (m, 1H); 1.46 (d, 3H). Federal Police. 237.4. The compound is isolated in a crystalline form.

Example 6 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methyl-amide

Para-toluenesulfonic acid monohydrate (0.20 g) was added to a solution of example 1b (0.65 g) in THF (6.5 ml) at 23 ° C under a nitrogen atmosphere. Isooctane (10 ml) was added and the suspension was stirred at 23 ° C for 24 hours. The solid was removed by filtration and dried at 23 ° C for 18 hours to give the title compound (0.567 g). NMR (d 6 -DMSO): δ (ppm) 9.53 (broad s, 1H); 8.00 (bs, 1H); 7.68 (bs, 2H); 7.46 (d, 2H); 7.22 (broad m, 1H); 7.10 (d, 2H); 6.95 (dd, 1H); 6.82 (m, 1H); 5.30 (q, 1H); 4.45 (broad d, 1H); 4.19 (d, 1H); 3.99 (broad m, 5H); 3.65-3.05 (m, 3H); 3.05-2.70 (m, 2H); 2.73 (s, 3H); 2.35 (s, 3H); 2.27 (s, 3H); 2.12 (m, 1 H); 2.07 (m, 1 H); 2.02 (s, 3H); 1.87 (m, 1H); 1.72 (m, 1H); 1.46 (d, 3H). 61 ΡΕ1524266

EXAMPLES 7 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 5-bis-trifluoromethyl-benzyl) -methylamide (7a)

4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, bis-trifluoromethyl-benzyl) -methylamide (7b)

A solution of intermediate 10 (86.7 mg), 1-acetylpiperazine (22 mg) and sodium triacetoxyborohydride (67 mg) in dry 1,2-dichloroethane (5 ml) was stirred at 23øC for 24 hours under an atmosphere of nitrogen. The solution was washed with 5% sodium hydrogen carbonate solution (15 ml) and brine (10 ml). The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / MeOH 7: 3) to yield: 1. 4- (R) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl-benzyl) -methylamide (34.6 mg, hereinafter compound 1) ; 2. 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, Bis-trifluoromethyl-benzyl) -methylamide (19 mg, hereinafter compound 2). 62 ΡΕ1524266

Example 7a

A solution of compound 1 (33 mg) in dry Et 2 O (2 mL) was treated with hydrochloric acid (1 M in Et 2 O - 0.5 mL). The resulting solution was stirred at 23 ° C for 30 minutes. The solution was concentrated in vacuo to give the title compound as a white foam (30 mg). IR (nujol, cm -1): 3395 (NH +), 1632 (C = O). NMR (d6 -DMSO): δ (ppm) 10.35 (bs, 1H); 7.98 (bs, 1H); 7.8 (bs, 2H); 7.37 (dd, 1H); 7.0 (dd, 1H); 6.92 (m, 1H); 5.24 (m, 1H); 4.57 (d, 1H); 4.41 (d, 1H); 4.45 (broad m, 1H); 3.99 (broad m, 1H); 3.8-3.4 (broad m, 6H); 3.2-2.8 (m, 4H); 2.73 (s, 3H); 2.34 (2H); 2.23 (s, 3H); 2.03 (s, 3H); 2.17 (1H); 1.69 (m, 1H). MS (ES +): m / z = 603 [MH-HCl] +.

Example 7b

A solution of compound 2 (19 mg) in dry Et2O (5 mL) was treated with hydrochloric acid (1M in Et2O - 1 mL). The resulting mixture was stirred at 23 ° C for 15 minutes, then concentrated in vacuo to give the title compound as a white foam (14 mg). IR (nujol, cm -1): 3387 (NH +), 1652 (C = O). NMR (d 6 -DMSO): δ (ppm) 11.77 (broad s, 1H); 7.94 (s, 1H); 7.58 (s, 2H); 7.24 (t, 1H); 6.93 (dd, 1H); 6.81 (m, 1H); 4.62 (d, 1H); 4.4 (dd, 1H); 4.35 (d, 1H); 4.19 (dd, 1H); 3.8-3.4 (m, 4H); 3.2-2.7 (m, 4H); 3.9-1.25 (m, 6H); 2.92 63 ΡΕ1524266 (s, 3H); 2.35 (s, 3H); 2.00 (s, 3H). MS (ES +): m / z = 603 [MH-HCl] +, 625 [M-HCl + Na]

Example 8 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide

A solution of intermediate 4a (100 mg), N-methylpiperazine (22 μ) and sodium triacetoxyborohydride (64 mg) in dry 1,2-dichloroethane (5 ml) was stirred at 23 ° C for 6 hours under an atmosphere of nitrogen. The solution was washed with 5% sodium hydrogencarbonate solution (10 ml) and brine (10 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (AcOEt / MeOH 95: 5 to 8: 2) to give 2- (R) - (4-fluoro-2-methylphenyl) -4- (R, S) - (4-methyl-1-piperazinyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethylphenyl) -ethyl] -methylamide (57 mg Tlc: AcOEt / MeOH 8: 2, Rf = 0.2) which was dissolved in dry Et2 O (5 ml) and then treated with hydrochloric acid (1M in Et2O 2 ml) and the resulting solution was stirred at 23Â ° C for 5 minutes. The solution was concentrated in vacuo to give a solid which was triturated in Et 2 O (2 mL) to give the title compound as a white solid (35.4 mg). IR (nujol, cm-1): 3405 (NH2 +), 1639 (C = O). NMR (d6 -DMSO): δ (ppm) 7.95 (s, 2H); 7.71 (s, 2H); 7.67 (s 64 ΡΕ1524266 2Η); 7.26 (dd, 1 Η); 7.15 (dd, 1H); 6.93 (dd, 1H); 6.87 (dd, 1H); 6.82 (m, 1H); 6.74 (m, 1H); 5.32 (q, 1H); 5.16 (q, 1H); 4.84 (m, 1H); 4.12 (dd, 1H); 3.5-3.0 (m, 3H); 2.69 (s, 3H); 2.61 (s, 3H); 2.32 (s, 3H); 2.24 (s, 3H); 2.13 (s, 3H); 2.09 (s, 3H); 2.5 - 1.5 (m, 12H); 1.50 (d, 3H); 1.45 (d, 3H). MS (ES +): m / z = 589 [MH-HCl]

Example 9 2- (R) - (4-Fluoro-2-methyl-phenyl) -4- (S) -piperazin-1-yl-piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide

A solution of intermediate 4a (160 mg), N-tert-butoxycarbonylpiperazine (60 mg) and sodium triacetoxyborohydride (100 mg) in dry 1,2-dichloroethane (12 ml) was stirred at 23 ° C for 24 hours. hours under a nitrogen atmosphere. The solution was washed with 5% sodium hydrogencarbonate solution (20 ml) and brine (20 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (CH / AcOEt from 1: 1 to 3: 7) to give: 1. 2- (R) - (4-Fluoro-2- (R) - [(4-tert-butoxycarbonyl) -piperazin-1-yl] -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl- phenyl) -ethyl] -methylamide (74 mg -Tlc: CH / AcOEt 1: 1, Rf = 0.35, hereinafter compound 1) 2. 2- (R) - (4-Fluoro-2-methyl -phenyl) -4- (S) - [(4-tert-butoxycarbonyl) -piperazin-1-yl] -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl- -ethyl] -methylamide (48 mg - Tlc: CH / AcOEt 1: 1,

Rf = 0.19 hence compound 2)

Trifluoroacetic acid (1 ml) was added dropwise at 0 ° C to a solution of compound 2 (48 mg) in dry DCM (3 ml). The solution was stirred for 1 hour at the same temperature and for 1 hour at r.t. Then the solvent was removed in vacuo and the crude material dissolved in AcOEt (5 ml). The resulting solution was washed with saturated potassium carbonate solution and dried. After concentration in vacuo, 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (S) -piperazin-1-yl-piperidine-1-carboxylic acid, [1- (R) - 3,5-bis-trifluoromethyl-phenyl) ethyl] -methylamide (18 mg) was dissolved in dry Et2O (1 ml) and was then treated with hydrochloric acid (1M in Et2O2 -220) at 0 ° C. The resulting mixture was stirred at r.t. for 30 minutes, then filtered and triturated with n-pentane to give the title compound as an off-white solid (15 mg). IR (nujol, cm-1): 1653 (C = O). NMR (d 6 -DMSO): δ (ppm) 7.94 (s, 1H); 7.59 (s, 2H); 7.22 (dd, 1H); 6.89 (dd, 1H); 6.77 (m, 1H); 4.62 (d, 1H); 4.36 (d, 1H); 4.13 (dd, 1H); 3.44 (m, 1H); 3.3 (m, 1H); 2.9 (s, 3H); 2.67 (m, 1H); 2.65 (m, 4H); 2.4 (broad m, 4H); 2.34 (s, 3H); 1.86 (broad d, 1H); 1.77 (broad d, 1H); 1.6 (dq, 1H); 1.34 (q, 1H). MS (ES +): m / z = 561 [MH-HCl] +. 66 ΡΕ1524266

Example 10 2- (R) - (4-Fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, 3,5-bis-trifluoromethyl-benzyl) -methylamide

A solution of intermediate 10 (120 mg) and N-methylpiperazine (41 μ) in dry 1,2-dichloroethane (2 ml) and acetonitrile (2 ml) was stirred at r.t. for 1 hour under a nitrogen atmosphere. Sodium triacetoxyborohydride (78 mg) was then added and the mixture was stirred at 23 ° C for 18 hours. The solution was washed with 5% sodium hydrogencarbonate solution (10 ml) and extracted with DCM (2 x 10 ml). The combined organic extracts were washed with brine (10 ml), dried and concentrated in vacuo to a residue, which was purified by flash chromatography (EtOAc / MeOH 1: 1) to give 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methylpiperazin-1-yl) -piperidine-1-carboxylic acid, (3,5-bis-trifluoromethyl) -benzylmethylamide Rf = 0.09), which was dissolved in Et 2 O (5 ml) then treated with hydrochloric acid (1 M in Et 2 O - 0.5 ml) and the resulting mixture was stirred at 23 ° C for 5 minutes. The mixture was concentrated in vacuo to a solid which was triturated in Et 2 O (2 mL) to give the title compound as an off-white solid (115 mg). M.p .: 208-9 ° C. 67 ΡΕ1524266 IR (nujol, cm -1): 3384 (NH +), 1645 (C = O). NMR (de-DMSO): δ (ppm) 7.9 (s, 1H); 7.7 (s, 1H); 7.59 (s, 1H); 7.4 (s, 1H); 7.24 (t, 1H); 6.95-6.82 (m, 2H); 4.63 (d, 1H); 4.59 (d, 1H); 4.36 (d, 1H); 4.21 (d, 1H); 4.19 (d, H); 2.93 (s, 3H); 2.37 (s, 3H); 2.27 (s, 3H); 3.7-1.0 (m, 17H). MS (ES +): m / z = 575 [M + H-2HCl] +.

Example 11 4- (R) - (4-Cyclopropanoylpiperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine- ) - (4-cyclopropanyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -ethyl] -2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl]

A solution of intermediate 4a (100 mg) and intermediate 12 (31 mg) in dry 1,2-dichloroethane (5 ml) and acetonitrile (1 ml) was stirred at r.t. for 30 minutes under a nitrogen atmosphere. Thereafter, sodium triacetoxyborohydride (42 mg) was added and the mixture was stirred at 23 ° C for 24 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / MeOH 9: 1) to give: Example 11a (2 mg - Tlc: AcOEt / MeOH 8: 2 Rf = 0.33) , Example 11b (7 mg - Tlc: AcOEt / MeOH 8: 2 Rf = 0.16). 68 ΡΕ1524266

Example 12 4- (S) - (4-Cyclopropanoyl-piperazin-1-yl) -2- (r) - (4-fluoro-2-methyl-phenyl) -piperidine- 1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide

A solution of Example 11b (7 mg) in dry Et 2 SO 4 (5 mL) was treated with hydrochloric acid (1 M in Et 2 O - 40 μ). The resulting mixture was stirred at 23øC for 15 minutes, then concentrated in vacuo to give the title compound as an off-white solid (7.2 mg). IR (nujol, cm-1): 3395 (NH +), 1644 (C = O). NMR (d 6 -DMSO): δ (ppm) 10.13 (broad s, 1H); 8.0 (broad s, 1H); 7.69 (s, 2H); 7.23 (m, H); 6.96 (m, 1H); 6.84 (m, 1H); 5.31 (broad q, 1H); 4.44 (bm, 2H); 4.2 (broad d, 1H); 3.7-2.9 (broad m, 5H); 2.8 (t, 4H); 2.75 (s, 3H); 2.37 (s, 3H); 2.16 (m, 2H); 1.99 (m, 1H); 2.0-1.5 (m, 2H); 1.47 (d, 3H); 0.87 (m, 2H); 0.74 (m, 2H). MS (ES +): m / z = 643 [MH-HCl] +.

Example 13 4- (R) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine- [1- (R) - (3,5-Bis-trifluoromethyl-phenyl) -ethyl] -methylamide (13a) yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (13b)

A solution of intermediate 4a (100 mg) and intermediate 14 (30 mg) in dry 1,2-dichloroethane (5 ml) was stirred at r.t. for 30 minutes under a nitrogen atmosphere. Thereafter, sodium triacetoxyborohydride (42 mg) was added and the mixture was stirred at 23 ° C for 24 hours. The solution was diluted with EtOAc and washed with water. The organic phase was dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt / MeOH 9: 1 to 8: 2) to give: Example 13a (15 mg - Tlc: AcOEt / MeOH 8: 2 Rf = 0.33), example 13b (27.5 mg - Tlc: AcOEt / MeOH 8: 2 Rf = 0.25).

Example 14 4- (S) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (r) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid , [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide hydrochloride

A solution of Example 13b (27.5mg) in dry Et 2 O (1ml) was treated with hydrochloric acid (1M in Et 2 O - 60μ). The resulting mixture was stirred at 23øC for 15 70 Å 2424266 minutes, then concentrated in vacuo. The residue was triturated with pentane to give the title compound as an off-white solid (25.8 mg). IR (nujol, cm -1): 3395 (NH +), 1641 (C = O). NMR (de-DMSO): δ (ppm) 10.37 (bs, 1H); 8.0 (s, 1H); 7.68 (s, 2H); 7.22 (dd, 1H); 6.94 (dd, 1H); 6.83 (bt, 1H); 5.31 (broad q, 1H); 4.46 (broad m, 1H); 4.18 (broad d, 1H); 4.12 (m, 1H); 3.6-3.4 (m, 5H); 3.1-2.7 (m, 5H); 2.73 (s, 3H); 2.36 (s, 3H); 2.18-2.11 (m, 2H); 1.89 (br q, 1H); 1.73 (q, 1H); 1.46 (d, 3H); 0.98 (broad s, 6H).

Example 15 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -piperazine-1-carboxylic acid, dimethylamide hydrochloride

TEA (74.6 μ) and triphosgene (13.2 mg) were added to a solution of example 17 (50 mg) in anhydrous DCM (2 ml) under a nitrogen atmosphere. The solution was stirred at 23 ° C for 2 hours, then DIPEA (31.9 μ) and dimethylamine (2M solution in THF - 49 μΐ) were added. The mixture was stirred at 23 ° C for 18 hours, then placed in a 1 M hydrochloric acid solution (10 ml) and extracted with AcOEt (2 x 20 ml). The combined organic extracts were dried and concentrated in vacuo to give 4- (S) - [1 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro- -2-methyl-phenyl) -piperidin-4-yl] -piperazine-1-carboxylic acid, dimethylamide (60 mg).

A solution of this compound (60 mg) in dry Et 2 O (1 ml) was treated with hydrochloric acid (1 M in Et 2 O - 100 μ). The resulting mixture was stirred at 23 ° C for 15 minutes, then concentrated in vacuo. The residue was triturated with petroleum ether to give the title compound as an off-white solid (52 mg). IR (nujol, cm -1): 3382 (NH +), 1652 (C = O). NMR (DMSO): δ (ppm) 10.34 (bs, 1H); 7.95 (s, 1H); 7.59 (s, 2H); 7.28 (m, 1H); 6.94 (dd, 1H); 6.84 (m, 1H); 4.63 (d, 1H); 4.36 (d, 1H); 4.2 (dd, 1H); 3.6-3.4 (m, 5H); 3.4-4.1 (m, 5H); 2.93 (s, 3H); 2.75 (s, 6H); 2.7 (m, 1H); 2.36 (s, 3H); 2.17 (m, 2H); 1.9 - 1.65 (m, 2H). MS (ES +): m / z = 632 [MH-HCl] +.

Example 16 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -1-carboxylic acid, methylamide hydrochloride

TEA (74.6 μ) and triphosgene (13.2 mg) were added to a solution of example 17 (50 mg) in anhydrous DCM (2 ml) under a nitrogen atmosphere. The solution was stirred at 23 ° C for 2 hours, then DIPEA (31.9 μ) and methylamine (2 M solution in THF - 49 μΐ) were added. The mixture was stirred at 23 ° C for 18 hours, then placed in a 1 M hydrochloric acid solution (10 ml) and extracted with AcOEt (2 x 20 ml). The combined organic extracts were dried and concentrated in vacuo to give 4- (S) - [1 - [(3,5-bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4 -fluoro-2-methyl-phenyl) -piperidin-4-yl] -1-carboxylic acid, methylamide (65.3 mg).

A solution of this compound (60 mg) in dry Et 2 O (1 ml) was treated with hydrochloric acid (1 M in Et 2 O - 100 μ). The resulting mixture was stirred at 23 ° C for 15 minutes, then concentrated in vacuo. The residue was triturated with petroleum ether to give the title compound as an off-white solid (55 mg). IR (nujol, cm -1): 3351 (NH +), 1652 (C = O). NMR (d 6 -DMSO): δ (ppm) 10.35 (bs, 1H); 7.95 (s, 1H); 7.59 (s, 2H); 7.25 (m, 1H); 6.94 (dd, 1H); 6.84 (m, 1H); 6.68 (bs, 1H); 4.63 (d, 1H); 4.36 δ (d, 1H); 4.18 (dd, 1H); 4.0 (m, 1H); 3.6-3.4 (m, 5H); 3, 1-2.9 (m, 4H); 2.93 (s, 3H); 2.73 (m, 1H); 2.56 (s, 3H); 2.36 (s, 3H); 2.19 (m, 2H); 1.9 (m, 1H); 1.7 (m, 1H) MS (ES +): m / z = 618 [MH-HCl] +.

Example 17 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin-4 -yl] -piperazine

TFA (1 ml) was added to a solution of intermediate 15b (155 mg) in anhydrous DCM (5 ml). The solution was stirred at r.t. for 3 hours, then concentrated in vacuo. The residue was diluted in a potassium carbonate saturated solution (10 ml) and extracted with DCM (2 x 20 ml) and AcOEt (20 ml). The combined organic extracts were dried and concentrated in vacuo to give the title compound (104 mg) as an oil. T.l.c .: AcOEt / MeOH 8: 2 Rf = 0.12. IR (nujol, cm 4): 1653 (C = O). NMR (de-DMSO): δ (ppm) 7.94 (s, 1H); 7.59 (s, 2H); 7.22 (dd, 1H); 6.89 (dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.36 (d, 1H); 4.13 (dd, 1H); 3.44 (dt, 1H); 3.3 (m, 1H); 2.9 (s, 3H); 2.67 (m, 1H); 2.65 (m, 4H); 2.4 (broad m, 4H); 2.34 (s, 3H); 1.86 (broad d, 1H); 1.77 (broad d, 1H); 1.6 (dq, 1H); 1.34 (q, 1H). MS (ES +): m / z = 561 [MH] +.

Example 18 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid [1- (R) 5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide (18a)

4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenylpiperidine-1-carboxylic acid, [1- (R) - (3,5-bis trifluoromethyl-phenyl) -ethyl] -methylamide (18b)

A solution of intermediate 20a (140 mg), 1-acetylpiperazine (73 mg) and sodium triacetoxyborohydride (121 mg) in dry acetonitrile (8 ml) was stirred at 23øC for 24 hours under a nitrogen atmosphere. Thereafter, additional sodium triacetoxyborohydride (60 mg) was added and the solution was stirred for an additional 1 hour 74 ΡΕ1524266. The solution was diluted with EtOAc (20 ml) and washed with a saturated solution of sodium hydrogen carbonate (15 ml) and brine (10 ml). The organic phase was dried and concentrated in vacuo to a residue, which was purified by flash chromatography (EtOAc / MeOH 9: 1 to 8: 2) to give: compound 18a (4 mg) T.l.c .: AcOEt / MeOH 8: 2

Rf = 0.48); Compound 18b (20 mg) T.l.c .: AcOEt / MeOH 8: 2

Rf = 0.40).

Example 19 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl-methylamide

A solution of 18b (20 mg) in dry Et 2 O (1 mL) was treated at -8 ° C with hydrochloric acid (1M in Et 2 O - 0.5 mL). The resulting mixture was stirred at 0 ° C for 10 minutes, then filtered; the filtrate was triturated with dry pentane (2 x 2 mL) to give the title compound as an off-white solid (14.7 mg). NMR (d 6 -DMSO): δ (ppm) 10.15 (broad s, 1H); 7.91 (s, 1H); 7.68 (s, 2H); 7.26 (m, 2H); 7.01 (m, 2H); 5.28 (q, 1H); 4.4 (broad d, 1H); 4.09 (dd, 1H); 3.8-3.4 (m, 5H); 3.8-2.8 (m, 4H); 3.1-2.7 (m, 4H); 2.01 (s, 3H); 2.2-1.8 (m, 4H); 1.47 (d, 3H). MS (ES +): m / z = 603 [MH-HCl] +. 75 ΡΕ1524266

Pharmaceutical Examples A. Capsules / Tablets

Active ingredient 20.0 mg Starch 1500 2.5 mg Microcrystalline Cellulose 200.0 mg Croscarmellose Sodium 6.0 mg Magnesium Stearate 1.5 mg The active ingredient is mixed with the other excipients. The blend may be used to fill gelatin capsules or compressed into tablets using suitable punches. The tablets may be coated using conventional techniques and coatings. B. Tablets

Active Ingredient 20.0 mg Lactose 200.0 mg Microcrystalline Cellulose 70.0 mg Povidone 25.0 mg Croscarmellose Sodium 6.0 mg Magnesium Stearate 1.5 mg The active ingredient is mixed with lactose, microcrystalline cellulose and part of croscarmellose of sodium. The mixture is granulated with povidone after dispersion in a suitable solvent (i.e. water). The granule, after drying and fragmentation, is mixed with the remaining excipients. The blend may be compressed using suitable punches and the coated tablets using conventional techniques and coatings. c) Cake 2-60 mg / ml 1.0-50.0 mg / ml qb for 1 ml

Active ingredient Sodium phosphate water for injection The formulation may be packed in glass ampoules or vials and syringes with a rubber stopper and a plastic / metal cap (for vials only). D) Infusion

Active ingredient 2-60 mg / ml

Infusion solution (0.9% NaCl or 5% dextrose) qb to 100 ml The formulation may be packed in glass vials or plastic bag. The affinity of the compound of formula (I) for the NK 1 receptor was determined using the χ 2 receptor binding affinity method by measuring in vitro the 77 ΡΕ1524266 ability of the compounds to replace the [3H] -substance P (SP) of recombinant human NKi expressed on Chinese Hamster Ovary (CHO) cell membranes. The affinity values are expressed as the negative logarithm of the inhibition constant (Ki) of the substituent ligands (pKi).

The pKi values obtained as the mean of at least two determinations with representative compounds of formula (I) are given in the following table:

Example No PK 2 9, 36 3 10.29 7a 9.15 7b 10.13 8 kQ 9 9.9 93 10 9, 94 12 9, 91 14 10.00 15 10.34 16 10.36 19 9,38 The ability of the compounds of formula (I) to penetrate the central nervous system and to bind to the N kg receptor can be determined using the gerbil leg tremor model 78 ΡΕ1524266 as described by Rupniak & Williams, Eur. Jour. of Pharmacol., 1994. The compound was administered orally and four hours later an NKi agonist (eg delta-Aminovaleryl6 [Pro9, MeLeu10] -P (7-11)) was introduced by infusion (3 pmol in 54 μ icv) in the cerebral ventricles of the animals. The duration of hind paw tremor induced by the NK1 agonist (e.g. delta-Aminovaleryl6 [Pro9, Me-Leu10] -substance P (7-11)) was continuously recorded for 3 min using a stopwatch. The dose of the test compound required to 50% inhibit tremor induced by the NKi agonist (eg delta-Aminovaleryl6 [Pro9, Me-Leu10] -substance P (7-11)) expressed as mg / kg is referred to as the ED 50 values . Alternatively the compounds may be administered subcutaneously or intraperitoneally.

The representative results obtained for the compounds of formula (I) when given by oral administration are shown in the following table

Ex ED50 (mg / kg) 3 0.05 7b 0.19 12 0, 27

Examples 47, 49 and 52 disclosed in WO 97/16440 did not show in the tremor model of the 79 ΡΕ1524266 gerbil leg any capacity up to 1 mg / kg to penetrate the central nervous system when administered orally 4 hours prior to administration of an NK 1 agonist (eg delta-Aminovaleryl 6 [Pro 9, Me-Leu 10-substance P (7-11)) (3 pmol in 54 μl icv). No adverse effects were observed when the compounds of formula (I) were administered to the gerbil at the pharmacologically active doses.

Lisbon, May 21, 2007

Claims (14)

A composition comprising a compound of formula (I) (I) wherein R represents a halogen atom or a C 1-4 alkyl group; R1 represents a C1-4 alkyl group; R2 represents hydrogen or a C4-4 alkyl group; R3 represents hydrogen, or a C4-4 alkyl group; R4 represents a trifluoromethyl group; R5 represents hydrogen, a C4-4 alkyl or C (O) R6 group; R6 represents C4-4 alkyl, C3-7 cycloalkyl, NH (C1-4 alkyl) or N (C1-4 alkyl) 2; m is zero or an integer from 1 to 3; n is an integer from 1 to 3 or pharmaceutically acceptable salts or solvates thereof and a selective serotonin reuptake inhibitor. 2 ΡΕ1524266 A composition as claimed in claim 1 wherein the compound of formula (I) is selected from: 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4- fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- trifluoromethyl-benzyl) -methylamide; 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- trifluoromethyl-benzyl) -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (S) -piperazin-1-yl-piperidine-1-carboxylic acid, [1- (R) - (3,5-bis trifluoromethyl-phenyl) -ethyl) -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, 5-bis-trifluoromethyl-benzyl) -methylamide; 4 - (S) - (4-cyclopropanoyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - (4-Cyclopropanoylpiperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - 3β, 15β-2,66 (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -piperazine-1-carboxylic acid, dimethylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -1-carboxylic acid, methylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin-4-yl ] -piperazine; 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethylphenyl) -ethyl] -methylamide; or pharmaceutically acceptable salts or solvates thereof. A composition as claimed in claim 1 or 2 wherein the compound of formula (I) is 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4- fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide or pharmaceutically acceptable salts or solvates thereof. 4 ΡΕ1524266 A composition according to any one of claims 1 to 3 wherein the compound of formula (I) is 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide methanesulfonate. A composition according to any one of claims 1 to 4 wherein the selective serotonin reuptake inhibitor is selected from fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline or zimeldine. A composition according to any one of claims 1 to 5 wherein the compound of formula (I) is 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide methanesulfonate and the serotonin reuptake inhibitor selective is citalopram. A composition according to any one of claims 1 to 6 for use in the treatment and / or prophylaxis of depression and / or anxiety. A pharmaceutical formulation comprising a composition according to any one of claims 1 to 6 together with one or more pharmaceutically acceptable carriers or excipients. 5 ΡΕ1524266 The use of a compound of formula (I) and a selective serotonin reuptake inhibitor in the manufacture of a medicament for simultaneous or sequential administration for the treatment and / or prophylaxis of depression and / or anxiety. The use according to claim 9 wherein the compound of formula (I) is selected from 4- (R) - (4-acetyl-piperazin-1-yl) -2- (R) - (4- fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- trifluoromethyl-benzyl) -methylamide; 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, (3,5- trifluoromethyl-benzyl) -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (S) -piperazin-1-yl-piperidine-1-carboxylic acid, [1- (R) - (3,5-bis trifluoromethyl-phenyl) -ethyl) -methylamide; 2- (R) - (4-fluoro-2-methyl-phenyl) -4- (R, S) - (4-methyl-piperazin-1-yl) -piperidine-1-carboxylic acid, 5-bis-trifluoro-6α, 15,246,6-methyl-benzyl) -methylamide; 4- (S) - (4-Cyclopropanoylpiperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, ) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - (4-Cyclopropanoylpiperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R ) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - [4- (2-methyl-propanoyl) -piperazin-1-yl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, 1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -piperazine-1-carboxylic acid, dimethylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin- 4-yl] -1-carboxylic acid, methylamide; 4- (S) - [1 - [(3,5-Bis-trifluoromethyl-benzyl) -methyl-carbamoyl] -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidin-4-yl ] -piperazine; 4- (S) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide; 4- (R) - (4-Acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-phenyl) -piperidine-1-carboxylic acid, [1- (R) , 5-bis-trifluoromethylphenyl) -ethyl] -methylamide; or pharmaceutically acceptable salts or solvates thereof. 7 ΡΕ1524266 The use according to claim 9 or 10 wherein the compound of formula (I) is 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4 2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide or pharmaceutically acceptable salts or solvates thereof. The use according to any one of claims 9 to 11 wherein the compound of formula (I) is 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide methanesulfonate. The use according to any one of claims 9 to 12 wherein the selective serotonin reuptake inhibitor is selected from fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalipine, sertraline or zimeldine. The use according to any one of claims 9 to 13 wherein the compound of formula (I) is 4- (S) - (4-acetyl-piperazin-1-yl) -2- (R) - (4-fluoro-2-methyl-phenyl) -piperidine-1-carboxylic acid, [1- (R) - (3,5-bis-trifluoromethyl-phenyl) -ethyl] -methylamide methanesulfonate and the serotonin reuptake inhibitor selective is citalopram. Lisbon, May 21, 2007